The present invention relates to novel piperazine derivatives which are of use in the treatment of pathologies associated with insulin-resistance syndrome.
The compounds of the invention have the formula: 
in which:
n represents 2, 3, 4, 5 or 6;
X represents O or S;
Ar represents an aromatic nucleus chosen from phenyl, pyridyl, pyrimidinyl, benzoxazolyl, benzothiazolyl and benzimidazolyl, the said aromatic nucleus optionally being substituted by one or more radicals chosen from a halogen atom; a (C1-C6) alkoxy group; a (C6-C10) aryloxy group; a (C6-C10)aryl(C1-C6)alkoxy group in which the aryl part is optionally substituted by halogen, (C1-C6)alkyl or (C1-C6)alkoxy; and a (C1-C6)alkyl group substituted by one or more halogen atoms;
i represents 0, 1, 2, 3 or 4; and
each Z group independently represents a halogen atom; as well as their addition salts with pharmaceutically acceptable bases or acids.
The invention also relates to the solvates of the compounds of formula I.
The term xe2x80x9calkylxe2x80x9d is understood to mean, according to the invention, a linear or branched hydrocarbon-comprising group. Mention may be made, as example of alkyl groups, of the methyl, ethyl, propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, isoamyl, tert-amyl, sec-amyl, pentyl and hexyl groups.
The alkyl parts of the alkoxy and arylalkoxy groups have the same definition as given above for the alkyl group.
Mention may be made, as example of alkyl groups substituted by one or more halogen atoms, of the perfluoroalkyl groups, such as trifluoromethyl or pentafluoroethyl.
The aryl group is a mono- or polycyclic aromatic group, preferably mono- or bicyclic, such as phenyl or naphthyl. The same definition is valid for the aryl parts of the aryloxy and arylalkoxy groups.
The halogen atoms are chosen from bromine, fluorine, iodine and chlorine.
When Ar represents substituted phenyl, the phenyl nucleus can carry one, two, three, four or five substituents. However, when Ar represents substituted phenyl, the phenyl nucleus is preferably mono-, di- or trisubstituted. In this case, the substituents are preferably in the meta or para position.
Examples of preferred aryloxy groups are phenoxy and naphthyloxy.
An example of a preferred arylalkoxy group is the benzyloxy group.
The xe2x80x94CH2xe2x80x94COOH group of the compounds of the invention is situated either in the ortho position or in the meta position or in the para position with regard to the chain 
However, preference is given to the compounds in which the xe2x80x94CH2xe2x80x94COOH group is in the para or ortho position, the para position being especially preferred.
The compounds of formula I have a carboxyl functional group and can be salified. They are then provided in the form of addition salts with organic or inorganic bases.
The addition salts with bases are, for example, pharmaceutically acceptable salts, such as the sodium salts, the potassium salts or the calcium salts, which are obtained by using the corresponding alkali metal or alkaline earth metal hydroxides as bases.
Mention may be made, as other types of addition salts with pharmaceutically acceptable bases, of the salts with amines and in particular glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine.
The compounds of formula I can also be salified with inorganic or organic acids and preferably pharmaceutically acceptable acids, such as hydrochloric acid, phosphoric acid, fumaric acid, citric acid, oxalic acid, sulphuric acid, ascorbic acid, tartaric acid, maleic acid, mandelic acid, methanesulphonic acid, lactobionic acid, gluconic acid, glucaric acid, succinic acid, sulphonic acid or hydroxypropane-sulphonic acid.
The salts of the compounds of formula I with acids and bases which are not pharmaceutically acceptable form another aspect of the invention. These salts are intermediate compounds of use in the preparation of the compounds of the invention. This is because the compounds of the invention can be isolated as intermediates in the form of one of their non-pharmaceutically acceptable salts, before conversion to a pharmaceutically acceptable compound.
A first group of preferred compounds is composed of the compounds of formula I in which X represents an oxygen atom.
Preference is more particularly given, among the compounds of the invention, to those in which n represents 2 or 3 and better still those in which n is 2.
Another group of preferred compounds is composed of the compounds in which Ar represents unsubstituted pyridyl, unsubstituted pyrimidinyl or optionally substituted phenyl. When Ar represents substituted phenyl, the phenyl group preferably carries one or two substituents chosen from (C1-C6)alkoxy, halogen, phenoxy, trifluoromethyl and benzyloxy. Better still, when Ar represents substituted phenyl, the phenyl group is substituted in the meta position by a (C1-C6)alkoxy group, a phenoxy group, a trifluoromethyl group or a halogen atom, such as a fluorine or chlorine atom.
Another group of preferred compounds is composed of the compounds of formula I in which i represents 1 or 0, preferably 0.
According to a preferred alternative form of the invention, when i is 1, the xe2x80x94CH2xe2x80x94COOH group is situated in the ortho position with regard to the chain 
and the Z substituent is in the para position with respect to this same chain.
A final group of preferred compounds is composed of the compounds of formula I in which the xe2x80x94CH2xe2x80x94COOH group is situated in the para position on the phenyl group with respect to the chain 
The invention also relates to two processes for the preparation of the compounds of formula I.
According to a first process, an aromatic compound of formula II: 
in which Z, X and i are as defined above for the formula I and P1 is a protective group for a carboxyl functional group, is reacted with a piperazine of formula III: 
in which n and Ar are as defined above for the formula I and Grp1 is a leaving group.
Among the protective groups for carboxyl functional groups, those generally described in Protective Groups in Organic Synthesis, Greene T. W. and Wuts P. G. M., published by John Wiley and Sons, 1991, and in Protective Groups, Kocienski P. J., 1994, Georg Thieme Verlag, may be suitable. It is possible, by way of example, to envisage the protection of the carboxyl functional group in the ester form: in this case, P1 represents (C1-C6)alkyl.
A halogen atom (for example chlorine or bromine), a (C6-C10)arylsulphonyloxy group, in which the aryl group is optionally substituted by one or more (C1-C6)alkyl groups, or a (C1-C6)alkylsulphonyloxy group, in which the alkyl group is optionally substituted by one or more halogen atoms, may be selected as example of a Grp1 group.
The operating conditions for the reaction of the compound II with the piperazine III will be easily determined by a person skilled in the art, this reaction being a nucleophilic substitution.
The reaction of the compound II with the piperazine III is advantageously carried out in a polar aprotic solvent in the presence of a base.
Examples of appropriate solvents are acetonitrile, dimethylformamide, acetone, dimethyl sulphoxide and halogenated hydrocarbons, such as dichloromethane or dichloroethane.
Use may be made, as particularly preferred base, of potassium carbonate.
According to a preferred embodiment, the reaction of II with III is carried out at a temperature of 50 to 120xc2x0 C., for example at reflux of acetonitrile, when the latter is chosen as solvent, in the presence of an alkali metal iodide, such as potassium iodide.
The amount of potassium iodide which has to be used is variable and depends essentially on the nature of the reactants, on the nature of the solvent and on the reaction temperature.
A catalytic amount of potassium iodide (less than 1 molar equivalent with respect to the compound II) is generally sufficient.
The reaction of the compound II with the compound III is stoichiometric. However, it may be possible to carry out the reaction in the presence of a slight excess of the piperazine III, in such a way that the molar ratio of III to II will generally be between 1 and 1.2.
The reaction of the compound II with the piperazine III leads to a compound of formula IV: 
in which P1, X, Z, i, n and Ar are as defined above, which compound is converted to a compound of formula I by deprotection of the carboxyl functional group.
The deprotection methods are those commonly used in the art. They are, for example, described in Protective Groups in Organic Synthesis, Green T. W. and Wuts P. G. M., published by John Wiley and Sons, 1991, and in Protective Groups, Kocienski P. J., 1994, Georg Thieme Verlag.
When P1 represents (C1-C6)alkyl, the deprotection can involve the saponification of the ester functional group, for example by the action of dilute sodium hydroxide solution.
The compounds of formula II are generally commercially available or easily prepared by following known techniques.
The compounds of formula III can be prepared by reaction of a piperazine of formula V: 
in which Ar is as defined above, with a compound of formula VIII:
Grp1xe2x80x94(CH2)nxe2x80x94Txe2x80x83xe2x80x83VIII
where Grp1 is as defined above and T is a leaving group identical to or different from Grp1 and preferably a better nucleofuge than Grp1,
A person skilled in the art knows in particular that a leaving group becomes increasingly labile as the corresponding negatively charged species resulting from the heterolytic cleavage of the bond increases in stability. In this particular instance, Txe2x88x92 must be more stable than Grp1xe2x88x92 in order for T to be a better nucleofuge than Grp1.
According to a preferred alternative form of the invention, Grp1 is a chlorine atom and T is a bromine atom.
The reaction of V with VIII is preferably carried out in a polar aprotic solvent chosen from those defined above, at a temperature of between 15 and 80xc2x0 C., preferably between 15 and 35xc2x0 C., for example at room temperature (20 to 25xc2x0 C.). Dimethylformamide is preferred, by way of solvents.
The reaction of the piperazine V with the compound VIII advantageously takes place in the presence of a base, such as potassium carbonate.
Another process of for the preparation of the compounds of formula I consist in reacting a piperazine of formula V 
in which Ar is as defined above for the formula I, with a carboxyl derivative of formula VI 
in which n, X, Z and i are as defined above for the formula I, P2 is a protective group for a carboxyl functional group and Grp2 represents a leaving group. P2 may take any one of the meanings of P1 above. Just as for P1, it is preferable for P2 to represent (C1-C6)alkyl. Grp2 is a leaving group, the meaning of which is not critical according to the invention. Grp2 can usually represent a halogen atom, a (C6-C10) aryl-sulphonyloxy group, in which the aryl part is optionally substituted by one or more (C1-C6)alkyl groups, or a (C1-C6)alkylsulphonyloxy group, in which the alkyl group is optionally substituted by one or more halogen atoms.
The reaction of the piperazine V with the compound VI may be carried out in any one of the polar aprotic solvents defined above, preferably in acetonitrile. The yields and the kinetics of the reaction are markedly improved when the reaction is carried out in the presence of a base and in particular in the presence of potassium carbonate.
The reaction may be carried out at a temperature of between 50 and 120xc2x0 C., for example at reflux of the acetonitrile, when the latter acts as solvent.
By way of example, the piperazine of formula V is reacted with at least one equivalent of the compound of formula VI, in acetonitrile, in the presence of 1.5 to 3 equivalents of K2CO3 with respect to the piperazine of formula V. The molar ratio of the compound of formula VI to the piperazine V is advantageously between 1 and 1.5, preferably between 1 and 1.2.
According to a preferred embodiment of the invention, the reaction of V with VI is carried out in the presence of an alkali metal iodide, such as potassium iodide. It can be of use to use up to 1 equivalent of alkali metal iodide with respect to the amount of piperazine V. Thus, the molar ratio of alkali metal iodide to the piperazine V may vary between 0.1 and 1.5 equivalents.
The reaction of the piperazine V with the compound VI results in a compound of formula VII: 
in which n, X, Z, Ar, i and P2 are as defined above, which compound is converted to a compound of formula I by deprotection of the carboxyl functional group.
The operating conditions for the deprotection reaction will be easily determined by a person skilled in the art according to the nature of the P2 group.
When P2 represents (C1-C6)alkyl, the deprotection can involve the saponification of the ester functional group, for example by the action of dilute sodium hydroxide solution.
The compounds of formula V are commercially available or easily prepared from commercial compounds.
The compounds of formula VI are easily prepared by reaction of a compound of formula IX 
in which P2, X, Z and i are as defined above for the formula VI, with a derivative of formula X
Axe2x80x94(CH2)nxe2x80x94Grp2xe2x80x83xe2x80x83X
where n and Grp2 are as defined above for the formula VI and A represents a leaving group identical to or different from Grp2 and preferably more nucleofugic than Grp2. According to a preferred embodiment of the invention, A is a bromine atom and Grp2 is a chlorine atom.
The operating conditions for this reaction will be easily determined by a person skilled in the art using his overall knowledge of organic chemistry.
The reaction of IX with X preferably takes place in a polar aprotic solvent in the presence of a base, at a temperature of between 15 and 120xc2x0 C.
By way of example, the compound IX may be reacted with 1 to 4 equivalents, preferably 1.4 to 3 equivalents, of the derivative X in acetonitrile, as solvent, in the presence of 1.5 to 3.5 equivalents of K2CO3 with respect to the amount of compound IX, at a temperature of between 40 and 120xc2x0 C. The molar ratio of K2CO3 to the compound X is advantageously between 0.8 and 1.2.
The compounds of the invention are of use in the treatment of pathologies associated with insulin-resistance syndrome (syndrome X).
Insulin resistance is characterized by a reduction in the action of insulin (cf. Presse Medicale, 1997, 26 (No. 14), 671-677) and is implicated in a large number of pathological conditions, such as diabetes and more particularly non-insulin-dependent diabetes (type II diabetes or NIDDM), dyslipidaemia, obesity, arterial hypertension and certain microvascular and macrovascular complications, such as atherosclerosis, retinopathies and neuropathies.
Reference may be made, in this respect, to, for example, Diabetes, Vol. 37, 1988, 1595-1607, Journal of Diabetes and its Complications, 1998, 12, 110-119, or Horm. Res., 1992, 38, 28-32.
The compounds of the invention in particular exhibit a strong hypoglycaemic or hypolipidaemic activity.
Another subject-matter of the present invention is therefore pharmaceutical compositions comprising, as active principle, a compound according to the invention.
The pharmacuetical compositions according to the invention can be presented in forms intended for administration by the parenteral, oral, rectal, permucosal or percutaneous route.
They will therefore be presented in the form of injectable solutions or suspensions or multi-dose bottles, in the form of coated or uncoated tablets, of dragees, of capsules, including hard gelatin capsules, of pills, of cachets, of powders, of suppositories or of rectal capsules, of solutions or of suspensions, for percutaneous use, in a polar solvent, for permucosal use.
The excipients which are suitable for such administrations are derivatives of cellulose or micro-crystalline cellulose, alkaline earth carbonates, magnesium phosphate, starches, modified starches or lactose for the solid forms.
For rectal use, cocoa butter or polyethylene glycol stearates are the preferred excipients.
For parenteral use, water, aqueous solutions, physiological saline or isotonic solutions are the most conveniently used vehicles.
The dosage can vary within wide limits according to the therapeutic indication and the administration route, as well as the age and the weight of the subject.
The invention therefore also relates to the use of the compounds of formula I in the preparation of medicaments intended for the treatment of diabetes.